Preservative-free single dose inhaler system

ABSTRACT

An aerosolization system includes a container that is configured to deliver a unit dosage of a liquid when squeezed a single time. The system also includes an aerosolizer that is constructed of a housing defining a mouthpiece, and an aerosol generator disposed in the housing. The aerosol generator includes a vibratable membrane having a front face and a rear face, and a vibratable element used to vibrate the membrane. Further, the housing includes an opening that is adapted to receive a unit dosage of the liquid from the container. The opening provides a liquid path to the rear face of the vibratable membrane.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/606,623, filed on Jan. 27, 2015, which is a continuation of U.S.patent application Ser. No. 14/039,254, filed on Sep. 27, 2013, now U.S.Pat. No. 9,004,061, which is a continuation of U.S. patent applicationSer. No. 13/004,662, filed on Jan. 11, 2011, now U.S. Pat. No.8,950,394, which claims priority from U.S. Provisional Application No.61/335,769, filed on Jan. 12, 2010, which are incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

This invention relates generally to a single dose inhaler and insulinformation containers. The inhaler dispenses aerosolized pharmaceuticalagents for local or systemic inhalation drug delivery to the lungs. Theinvention is particularly, but not exclusively, useful for delivery ofpreservative free doses of insulin for treating type I and/or type IIdiabetic patients.

BACKGROUND OF THE INVENTION

Various types of inhalers exist for aerosolizing liquids. For example,U.S. Pat. No. 5,586,550, incorporated herein by reference, describes aninhaler which comprises a dispensing apparatus in which a membrane withtapered apertures is vibrated such that liquid in contact with a rearface of the membrane is dispensed from a front face of the membrane asan aerosol.

While effective at nebulizing liquids, such inhalers may not beparticularly suited for certain applications, such as aerosolizing unitdoses of insulin for pulmonary delivery.

Hence, the invention provides inhalers for delivering doses in arepeatable and predictable fashion. As described hereinafter, theinhalers of the invention may find particular use in aerosolizing liquidinsulin for pulmonary delivery.

BRIEF SUMMARY OF THE INVENTION

The invention provides various aerosolization systems, includingcontainers for supplying liquid to inhalers, as well as methods fortheir use. In one exemplary embodiment, the invention provides anaerosolization system that comprises a squeezable container having aresilient container body. The container is configured to deliver a unitdosage of a liquid when squeezed a single time.

The system further includes an aerosolizer that comprises a housingdefining a mouthpiece, and an aerosol generator disposed in the housing.The aerosol generator comprises a vibratable membrane having a frontface and a rear face, and a vibratable element used to vibrate themembrane. Further, the housing includes an opening that is adapted toreceive a unit dosage of the liquid from the container. The openingprovides a liquid path to the rear face of the vibratable membrane.

In one aspect, the aerosolizer includes a hollow needle that isconfigured to pierce the squeezable container and to supply the liquidto the rear face of the vibratable membrane. Also, the squeezablecontainer may comprise a blister containing a single unit dosage. Forexample, the blister may comprise a blow-fill-seal container thatcontains a preservative free solution. The blister may further comprisea squeezable body containing the solution, a twist off top and a tabadapted to display information about the solution.

In a further aspect, the single unit dosage has a concentration in therange from about 200 insulin units (“IU”)/ml to about 800 IU/ml.

In another embodiment, the container comprises a bottle containing ofvolume of the liquid. In one aspect, the bottle may include a meteringvalve that permits dispensing of a discrete droplet of the liquid eachtime the bottle is squeezed. In other cases, the size of the droplet maybe controlled based at least in part on the diameter of the tip of thebottle and the viscosity of the liquid.

The invention further provides another aerosolization system thatcomprises a container in the form of an ampoule containing a capillarythat holds a single unit dosage of a liquid. The system also includes anaerosolizer comprising a housing defining a mouthpiece, and an aerosolgenerator disposed in the housing. The aerosol generator comprises avibratable membrane having a front face and a rear face, and avibratable element used to vibrate the membrane. Also, the housingincludes an opening that is adapted to receive a unit dosage of theliquid from the container. Further, the opening provides a liquid pathto the rear face of the vibratable membrane.

In one particular aspect, the ampoule further comprises a snap-off topand a snap-off bottom. The capillary is sized such that surface tensionin the capillary prevents leakage of the liquid after removal of the topbut prior to removal of the bottom.

A further embodiment of the invention provides an aerosolization systemhaving a container comprising a container body that holds a supply ofliquid, and a plunger device that is movable to dispense a single unitdosage of a liquid from the container upon operation of the plungerdevice a set distance. An aerosolizer comprises a housing defining amouthpiece, and an aerosol generator disposed in the housing. Theaerosol generator comprises a vibratable membrane having a front faceand a rear face, and a vibratable element used to vibrate the membrane.Further, the housing includes an opening that is adapted to receive aunit dosage of the liquid from the container. The opening provides aliquid path to the rear face of the vibratable membrane.

In one aspect, the container further includes a metering device that isrotated to control movement of the plunger in order to set a single unitdosage amount.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective, partial cut-away view of one embodiment of adispensing apparatus and squeezable container according to theinvention.

FIG. 2 is a more detailed view of the dispensing apparatus and containerof FIG. 1.

FIG. 3 is illustrates the dispensing device of FIG. 1, showing a moredetailed view of a seat for holding the container and a needle forsupplying dispensed liquid to an aerosol generator.

FIG. 4 is a perspective view of another embodiment of a dispensingapparatus and an a squeezable bottle according to the invention.

FIG. 4A is a cross sectional schematic view of a portion of the bottleof FIG. 4 in a closed position.

FIG. 4B is a cross sectional schematic view of a portion of the bottleof FIG. 4 in an open position.

FIG. 5 illustrates another embodiment of a container for dispensing aunit volume of a liquid according to the invention.

FIG. 6 illustrates the container of FIG. 5 when dispensing a unit volumeof liquid into the dispensing apparatus of FIG. 4.

FIG. 7 illustrates an embodiment of an ampoule for dispensing a unitvolume of a liquid according to the invention.

FIG. 8 illustrates the ampoule of FIG. 7 with an end removed.

FIG. 9 illustrates the ampoule of FIG. 8 with the top end also removedand being deposited into a dispensing apparatus.

FIG. 10 illustrates another embodiment of a container for dispensing aunit volume of a liquid into the dispensing apparatus of FIG. 4.

DETAILED DESCRIPTION OF THE INVENTION

Certain aspects of the invention describe an aerosolizing apparatuscomprising a housing defining a dispensing outlet, a vibratable membranehaving a front face exposed at the outlet and a rear face for receivinga liquid to be dispensed, and a vibrating mechanism connected to thehousing and operable to vibrate the membrane to dispense aerosol of theliquid through the membrane. A liquid delivery system is used to delivera metered quantity of the liquid from to the rear face of the membrane.In this way, a metered quantity of liquid is dispensable at the outletby operating the vibrating mechanism for an operating period sufficientto completely aerosolize the metered quantity of the rear face.

An advantage of such an apparatus is that it facilitates the dispensingof substantially all of the liquid coming into contact with the rearface of the membrane as a single dose, especially when the metered doseis relatively small in volume. By dispensing the entire dose, themembrane is essentially free of liquid from one dose to the next. Inthis way, it is thereby possible to avoid contact between liquid andambient air during periods of non-use between successive uses. Forpharmaceutical preparations this is particularly important since it mayobviate the need for the use of preservatives in the liquid and avoidsevaporative losses. For example, various preservative free insulinformulations that may be used include those described in copending U.S.application Ser. No. 13/004,662, entitled “Preservative Free InsulinFormulations and Systems and Methods for Aerosolizing” and filed on thesame date as the present application, previously incorporated byreference.

The liquid supply system in one embodiment may comprise a deformablethin-wall blister which contains a pharmaceutical agent. The supplysystem further comprises a mechanical press configured to deform thethin-walled blister such that a single, preservative free unit dose isdelivered. The press mechanism is provided with a dispensing stationprovided with a piercing needle operable to pierce the blister andrelease its content upon actuation.

In one aspect, the needle has two ends, with the first end protrudingfrom the surface of the dispensing station and a second end extending torear face of the aerosol generator. In use the blister is seated in thedispensing station and the press mechanism forces the blister toward theneedle which pierces through the thin wall. In this way, the needleprovides a conduit for moving the liquid from the blister to the rearface of the vibratable membrane. When the press mechanism is releasedthe blister expands and returns to its natural position. This expansioncreates a suction action which removes the liquid from the needle andprevents dry out and clogging.

In a further aspect, the blister has a bellows shaped geometry which canelastically expand and compress. The term elastically expand andcompress includes when the blister is fully compressed the internalstresses are still within the elastic range of the material in use,thus, the blister can return to its natural position when the pressmechanism is released. In one particular aspect, the pharmaceuticalagent fills at least 80% the internal volume of the blister and morepreferably more than 90% of the volume. This prevents movement of liquidwhich in some cases may cause aggregation of the composition.

Conveniently, the end of the needle may be positioned in close proximityto the rear face of the vibratable membrane. Further, the housing maydefine a duct communicating between an air inlet and an outlet port. Thedispensing outlet is located in the duct intermediate the air inlet andthe outlet port such that the front face of the membrane is exposed toair within the duct. The outlet port may be a mouthpiece for inhalationor an adapter for nasal use.

Such an arrangement is particularly useful in the administration ofinhaled pharmaceutical liquid products where it is required that a fineaerosol of liquid be entrained in an inhaled air flow passing throughthe mouthpiece. One example of such a liquid is an insulin composition.

Referring now to FIG. 1, one embodiment of an inhaler will be described.FIG. 1 illustrates a partially cut-away view of the single-dose-inhaler100 and a unit dose blister 201 package for supplying a metered quantityof insulin to the inhaler. Inhaler 100 comprises two subassemblies 102and 112. The first subassembly 102 defines a compartment for theelectronic circuitry and the batteries, and the second subassembly 112defines a housing with a dispensing outlet 105 and contains a vibratablemembrane aerosol generator 108 and a dispensing mechanism 104. Aerosolgenerator 108 has a front face exposed at the outlet duct 111 and a rearface 109 contacted in use by liquid to be dispensed. Aerosol generator108 is connected to the housing of subassembly 112 and is operable todispense the active pharmaceutical agent as an aerosol through themouthpiece 105. Exemplary aerosol generators that may be used are alsodescribed in U.S. Pat. Nos. 5,164,740; 6,629,646; 6,926,208; 7,108,197;5,938,117; 6,540,153; 6,540,154; 7,040,549; 6,921,020; 7,083,112;7,628,339; 5,586,550; 5,758,637; 6,085,740; 6,467,476; 6,640,804;7,174,888; 6,014,970; 6,205,999; 6,755,189; 6,427,682; 6,814,071;7,066,398; 6,978,941; 7,100,600; 7,032,590; 7,195,011, incorporatedherein by reference. These references describe exemplary aerosolgenerators, ways to manufacture such aerosol generators and ways tosupply liquid to aerosol generators, and are incorporated by referencefor at least these features. The aerosol generators may comprisevibratable membranes having tapered aperture with a size in the rangefrom about 3 μm to about 8 μm, preferably from about 3 μm to about 6 μm,and in some cases around 4 μm. The membrane may be domed shaped and bevibrated by an annular piezoelectric element that circumscribes theapertures. The diameter of the membrane may be in the range from about 5mm to about 8 mm. The membrane may also have a thickness in the rangefrom about 50 microns to about 70 microns. Typically, the membrane willbe vibrated at a frequency in the range from about 50 kHz to about 150kHz.

Each time the dispensing system is operated it delivers a meteredquantity of the liquid from the unit dose blister 201 to the rear face109 of the aerosol generator. Hence, for each use a metered quantity ofaerosolized pharmaceutical agent is dispensed at the mouthpiece outlet105 by operation of the aerosol generator.

The blister 201 contains a predetermined volume of an activepharmaceutical agent to be dispensed. In one embodiment the blister 201contains about 80 to about 120 micro-liters of insulin. The lower limitis typically at least about 15 micro-liters and the upper limit istypically about 1,000 micro-liters to about 2,000 micro-liters. Oneparticularly useful range is about 80 micro-liters to about 120micro-liters in a concentration of about 100 insulin units/ml orgreater, and more preferably between about 200-800 units/ml, and in somecases as high as 2,500 units/ml. Blister 201 is made of thin-walleddeformable material. Due to sensitivity of insulin to mechanicalagitation, the blister 201 is filled-up to nearly its entire volume.Specifically, more than 80% of the volume is filled with insulin.

Inhaler 100 further includes a dispensing station configured to dispensethe content of the blister 201 to the aerosol generator 108. Thedispensing station includes a swivel arm member 104 and a blister seat107. The blister seat 107 has a concave shape which may radially matchthe convex shape of the blister 201. The blister seat 107 furtherincludes a hypodermic needle 112 which establishes a fluid passage fromthe blister to the vibrating aerosol generator 108. The needle 112 hastwo sections. The first section 112A extends from the dispensing seatand protrudes outwardly perpendicularly to blister seat 107. The secondend 112B extends inwardly toward the aerosol generator 108 and ispositioned in closed proximity to rear side of the vibrating membrane ofaerosol generator 108. Typically, second end 112B will be less than 5 mmand more preferably less than 2 mm from the vibrating membrane of theaerosol generator 108. The hypodermic needle 112 may be made ofstainless steel alloy type 316 with a gage size ranging from 22 gage to26 gage. The first section 112A has a sharp slanted piercing tip. Inuse, blister 201 is placed upon the concave seat 107 and then the swivelarm 104 is rotated counter clockwise in the direction of arrow 115.

Conveniently, the force upon the swivel arm 104 may be applied by athumb against the curved portion of the arm 104. This action forces theblister toward the piercing tip of the needle 112A which subsequentlypierces the blister 201 and squeezes its content via the needle 112through the outlet of the needle 112B and onto the aerosol generator108. When the swivel arm 104 is fully depressed, the entire dose isdelivered to the vibrating membrane of the aerosol generator 108.

FIG. 2 illustrates the vibrating membrane 109 of the aerosol generator108 in greater detail. When the content of the blister 201 is fullydispensed an indicator light 120 starts to blink signaling to thepatient that the inhaler 100 is ready for use. At any time shortlythereafter the patient may inhale through the mouthpiece 105. Patientinhalation is detected by a flow sensor which in turn activates theaerosol generator 108 to produce aerosol particles into the duct 111.Aerosol is entrained in the inhalation air flow in the direction shownby arrows 121 and flow via the respiratory system to the lungs of thepatient. When the entire dose is aerosolized, which may take one ormorel breaths, the “end-of-dose” indicator light 121 lights a secondtime to signal the patient that the entire dose has been delivered.Delivery of the entire dose is obtained when at least about 95% of thedose is delivered, more preferably 98% and most preferably when morethan 99% of the dose is delivered. In one embodiment, the opening funnelto the aerosol generator is sufficiently large such that the liquiddelivery to the aerosol generator is delivered in its entirety. Toreceive the dose, the patient may take several inhalations or a singleinhalation depending on the volume delivered to the mesh and thepatient's breathing capacity. Each inhalation should be a deep breath toassure that the aerosol reaches deeply to the lungs.

When the end-of-dose indicator light 120 is actuated followinginhalation of the contents of blister 201, the empty blister may beremoved and discarded. When the thumb pressure on the swivel arm 104 isrelease the blister expands to its original shape. Expansion creates avacuum inside the blister 201 which draws back any adhered fluid fromthe needle back to the blister, thereby leaving the interior of theneedle dry to prevent material dry-out and clogging. To further preventpossible bacterial contamination the internal and/or the externalsurfaces of the needle, needle 112 may be coated with silver, a silverbased coating or the like.

FIG. 3 illustrates the concave seat 107 of the dispensing station ingreater detail. Seat 107 is provided with holes 117 which providesaccess to the interior of the inhaler in the vicinity of the aerosolgenerator 108. This permits cleaning solvents and rinsing water to besupplied to the aerosol generator 108.

FIG. 4 provides an alternative delivery system for an inhaler 500 whichutilizes a preservative free dispenser 550 and a nozzle 551 to dispensea volume of a preservative free pharmaceutical agent to the aerosolgenerator via an opening 501. Inhaler 500 can be constructed in a mannersimilar to inhaler 100 and may include a similar aerosol generator.Opening 501 has a funnel shape which tapers down to a small opening 502,thus forming a slope 503. Dispenser 550 is a uniform drop, preservativefree dispenser which upon activation displaces a single drop through thetip of its nozzle 551. Preferably, the drop volume is smaller than about200 micro-liters. A dose is dispensed by squeezing container 550 in adirection perpendicular to its longitudinal axis. Upon each actuation, asingle drop of a fixed volume is displaced through the nozzle 551.

One exemplary dispenser is the Aptar OSD dispenser, developed by Ing.Erich Pfeiffer GmbH. Such a container is constructed of a squeeze bottlethat is squeeze to dispense a droplet. When released, the nozzleprevents microbiological contaminants from entering into the remainingliquid. This is accomplished through a tip seal (see, for example, tipseal 560 of FIGS. 4A and 4B) that prevents back flow of liquid into thecontainer. As shown in FIG. 4A, the tip sealing mechanism includes aspring 562 that keeps the tip seal 560 in place in a normally closedposition. When squeezing the bottle, liquid passes between the seal 560and a cap until sufficient pressure is created to overcome the force ofthe spring 562 (see FIG. 4B). In this way, a single droplet can bedispensed. After dispensing, the tip seal again closes to preventliquids from moving back into the container. To relieve the accumulatingvacuum within the bottle, a small hole is included in the side of thecontainer to allow air into the spring chamber. Droplet size can becontrolled based on several factors including top size and the viscosityof the liquid.

In use, nozzle 551 is aligned with the opening 501 such that the drop isdispensed to the slope 503 and flows through the opening 502 to theaerosol generator. Preferably, the angle of slope 503 is greater thanabout 30 degrees relative to the axis of the opening 502. The diameterof opening 501 is about 10 mm to about 15 mm and the diameter of opening502 is at least about 5 mm. The pharmaceutical fluid in the preservativefree dispenser 550 may be contained in a collapsible sack to preventexcessive agitation and which may damaged by mechanical sloshing. Forexample, proteins, such as insulin, may be sensitive to mechanicalagitation. Use of a collapsible sack may limit undesirable agitation.

In another alternative embodiment, instead of using a container of thetype described in FIG. 5, a container 600 could be used. Container 600comprises a blister 602 manufactured using a blow-fill-seal process.Container 600 is similar to the container 201 of FIG. 1 in that when theblister 602 is squeezed a unit dosage amount is delivered.

Blister 602 comprises a squeezable body 604 having a tab 606 and a twistoff top 608. Body 604 is sized to hold a unit dosage of liquid, and tab66 may include various types of identifying information, such as the lotnumber, date, and the like. Twist off top 608 provides a easy way toopen blister 602 so that the liquid can be dispensed.

Referring also to FIG. 6, use of blister 602 in supplying a unit dose ofliquid to inhaler 500 will be described. When ready to receive atreatment, a user takes blister 602 and twists off top 608. Typically,blister 602 will be held upright so that no liquid escapes. In somecases, the opening formed when top 608 is removed may be sized smallenough to hinder liquid from escaping. Blister 602 is moved over opening501 and body 604 is squeezed to expel the complete volume of liquid 610into opening 501 where the liquid drains through opening 503 and to theaerosolizer. In this way, blister 602 functions as a hand squeezable,single use container for a preservative free solution. Use of ablow-fill-seal process is particularly advantageous in that the blister602 can be manufactured at low cost while still allowing the storage ofa preservative free solution. Also, the metering process is simple,requiring only the removal of the top and squeezing of the blister.

FIG. 7 illustrates an embodiment of an ampoule 700 for dispensing a unitvolume of a liquid to be aerosolized. Ampoule 700 comprises an elongatebody 702 defining a capillary that hold a unit volume of liquid 704.Ampoule 700 further includes a top end 706 and a bottom end 708 that maybe removed from body 702, such as by snapping them off. Body 702 may beconstructed of a generally rigid material that has sufficient rigidityto permit the two ends to be easily snapped off.

When ready to dispense the liquid into an inhaler, top end 706 isremoved as illustrated in FIG. 8. The surface tension in body 702prevents leakage of any liquid 704 when ampoule 700 is inverted, such aswhen inserting ampoule 700 into an inhaler.

FIG. 9 illustrates the ampoule of FIG. 8 after being inserted into aninhaler 720. Inhaler 720 may be constructed in a manner similar to theother embodiments described herein an includes electronics 722 that areemployed to control operation of an aerosol generator 724 having avibratable mesh 726. Inhaler 720 includes an elongate opening 730 intowhich ampoule 700 is inserted after end 706 is removed. Once in place,end 708 is snapped off which allows liquid 704 to drain from ampoule 700and onto the rear face of vibratable mesh 726 as illustrated in FIG. 9.As mesh 726 vibrates, the liquid is aerosolized and directed toward amouthpiece 732 where the patient can inhale the medicament. Followingaerosolization, ampoule 700 may be removed from inhaler 720 anddiscarded.

FIG. 10 illustrates another embodiment of a container 800 for dispensinga unit volume of a liquid into the dispensing apparatus 500 that waspreviously described in connection with FIG. 4. Container 800 comprisesa container body 802 defining a reservoir 804 for holding a volume ofliquid to be dispensed. A plunger 806 is employed to force liquid inreservoir 804 through a dispensing end 808 of container 800. Container800 also includes a geared metering mechanism 812 that is rotated or“dialed” in order to control the extent of movement of plunger 806.Further, an actuator 814 is pressed to move the plunger 806 by theamount permitted by metering mechanism 812. In this way, a user cansimply “dial a dose” of liquid using metering mechanism 812 and thenpress actuator 814 in order to dispense a metered amount of liquid intohole 501 where it will be supplied to the aerosolization mechanism.

Container 800 can be configured to be disposable or reusable. Whenreusable, reservoir 804 may comprise a cartridge that is inserted intothe space defined by reservoir 804. Exemplary volume sizes may be about1, 1.8 or 3 ml cartridges, which may be constructed of glass, LDPE orthe like.

The invention has now been described in detail for purposes of clarityand understanding. However, it will be appreciated that certain changesand modifications may be practiced within the scope of the appendedclaims.

What is claimed is:
 1. An aerosolization system, comprising: a housing comprising two lateral faces and a plurality of side walls extending between the two lateral faces, the housing defining a mouthpiece on one of the plurality of side walls and a liquid receptacle fluidly coupled to the mouthpiece, wherein the liquid receptacle defines an opening that extends through an exterior surface of one of the plurality of side walls of the housing at an inlet end of the opening and that is configured to receive a dosage of liquid from a tip of a container that is interfaced with the liquid receptacle such that at least a portion of the tip of the container is received within the liquid receptacle while a main body of the container remains external to the housing; an aerosol generator disposed within the housing, wherein during use the aerosol generator aerosolizes the dosage of liquid as a user inhales, the aerosol generator comprises: a membrane having a front face, a rear face, and a plurality of apertures that extend between the front face and the rear face, wherein the dosage of liquid is received onto the rear face of the membrane; and a vibratable element configured to vibrate the membrane to aerosolize the dosage of liquid; a flow sensor configured to detect fluid flow through the mouthpiece as a user inhales; a first light configured to indicate that the dosage of liquid has been manually dispensed from the tip of the container into a receiving chamber within the housing while the main body of the container remains external to the housing; a second light configured to indicate that the vibratable element has aerosolized the dosage of liquid and the entire dosage of liquid has been delivered to a user, wherein: the first and second lights are on a flat surface of one of the plurality of side walls of the housing aligned with the mouthpiece; delivery of the entire dosage comprises delivery of 98% or more of the liquid received onto the rear face of the membrane; the inlet end of the opening is positioned between, and in general alignment with, the mouthpiece and the first and second lights, with the first light, second light, and the opening being positioned on a same one of the plurality of side walls and the first light and the second light being oriented such that the first light and the second light are visible to the user while the user inhales through the mouthpiece; and a common plane that is generally parallel to the two lateral faces passes through each of the inlet end of the opening, an opening of the mouthpiece, and the first and second lights; and a controller coupled to the flow sensor and to the aerosol generator, wherein the controller activates the aerosol generator in response to a signal from the flow sensor indicating fluid flow through the mouthpiece, and wherein during use the controller activates the first light once the dosage of liquid is within the receiving chamber and the second light once the dosage of liquid is aerosolized and inhaled by the user.
 2. The aerosolization system of claim 1, wherein the first light blinks to indicate that the dosage of liquid is within the housing.
 3. The aerosolization system of claim 1, wherein the vibratable element vibrates the membrane from about 50 kHz to about 150 kHz.
 4. The aerosolization system of claim 3, wherein the second light blinks to indicate that the aerosol generator has aerosolized the dosage of liquid and the entire dosage of liquid has been delivered to the user.
 5. The aerosolization system of claim 1, wherein the liquid receptacle comprises a tapered wall that guides the dosage of liquid to the opening.
 6. The aerosolization system of claim 5, wherein the opening has an axis, and wherein the slope of the tapered wall is from 30 degrees to greater than perpendicular relative to the axis of the opening.
 7. The aerosolization system of claim 1, comprising a cover coupled to the housing, wherein the cover is configured to open and close to expose and cover the opening in the liquid receptacle.
 8. The aerosolization system of claim 1, wherein the liquid receptacle has a maximum receptacle diameter between about 10 mm to about 15 mm, and wherein the opening has a diameter of at least 5 mm.
 9. The aerosolization system of claim 1, comprises a bottle containing one or more dosages of liquid, and wherein the bottle is configured to dispense the dosage of liquid when the bottle is actuated.
 10. An aerosolization system, comprising: a housing comprising two lateral faces and a plurality of side walls extending between the two lateral faces, the housing defining a mouthpiece on one of the plurality of side walls and a liquid receptacle fluidly coupled to the mouthpiece, wherein the liquid receptacle defines an opening that extends through an exterior surface of one of the plurality of side walls of the housing at an inlet end of the opening and that is configured to receive a dosage of liquid from a tip of a container that is interfaced with the liquid receptacle such that at least a portion of the tip of the container is received within the liquid receptacle while a main body of the container remains external to the housing; an aerosol generator disposed within the housing, wherein the aerosol generator comprises: a membrane having a front face, a rear face, and a plurality of apertures that extend between the front face and the rear face, wherein the dosage of liquid is received onto the rear face of the membrane; and a vibratable element configured to vibrate the membrane to aerosolize the dosage of liquid; a first light configured to indicate that the dosage of liquid has been received within the housing from the tip of the container into a receiving chamber within the housing while the main body of the container remains external to the housing; a second light configured to indicate that the dosage of liquid has been aerosolized and that the entire dosage of liquid has been delivered to a user, wherein: the first and second lights are on a flat surface of one of the plurality of side walls of the housing aligned with the mouthpiece; delivery of the entire dosage comprises delivery of 98% or more of the liquid received onto the rear face of the membrane; the inlet end of the opening is positioned between, and in general alignment with, the mouthpiece and the first and second lights, with the first light, second light, and the opening being positioned on a same one of the plurality of side walls and the first light and the second light being oriented such that the first light and the second light are visible to the user while the user inhales through the mouthpiece; and a common plane that is generally parallel to the two lateral faces passes through each of the inlet end of the opening, an opening of the mouthpiece, and the first and second lights; and a controller coupled to the first light, wherein during use the controller activates the first light once the dosage of liquid is within the housing, and the second light when the entire dosage of liquid has been delivered to the user.
 11. The aerosolization system of claim 10, comprising a flow sensor coupled to the controller and configured to detect fluid flow through the mouthpiece as a user inhales, wherein the controller activates the aerosol generator in response to a signal from the flow sensor indicating fluid flow through the mouthpiece, wherein during use the vibratable element aerosolizes the dosage of liquid as the user inhales.
 12. The aerosolization system of claim 10, wherein the liquid receptacle comprises a tapered wall that guides the dosage of liquid to the opening.
 13. The aerosolization system of claim 10, comprises a bottle containing one or more dosages of liquid, and wherein the bottle is configured to dispense the dosage of liquid when the bottle is actuated.
 14. An aerosolization system, comprising: a housing comprising two lateral faces and a plurality of side walls extending between the two lateral faces, the housing defining a mouthpiece on one of the plurality of side walls and a liquid receptacle fluidly coupled to the mouthpiece, wherein the liquid receptacle defines an opening that extends through an exterior surface of one of the plurality of side walls of the housing at an inlet end of the opening and that is configured to receive a dosage of liquid from a tip of a container that is interfaced with the liquid receptacle such that at least a portion of the tip of the container is received within the liquid receptacle while a main body of the container remains external to the housing; an aerosol generator disposed within the housing, wherein the aerosol generator comprises: a membrane having a front face, a rear face, and a plurality of apertures that extend between the front face and the rear face, wherein the dosage of liquid is received onto the rear face of the membrane; and a vibratable element configured to vibrate the membrane to aerosolize the dosage of liquid; a first light configured to indicate that the dosage of liquid has been manually dispensed from the tip of the container into a receiving chamber within the housing while the main body of the container remains external to the housing; a second light configured to indicate that the vibratable element has aerosolized the dosage of liquid and the entire dosage of liquid has been delivered to a user, wherein: the first and second lights are on a flat surface of one of the plurality of side walls of the housing aligned with the mouthpiece; delivery of the entire dosage comprises delivery of 99% or more of the liquid received onto the rear face of the membrane; the inlet end of the opening is positioned between, and in general alignment with, the mouthpiece and the first and second lights, with the first light, second light, and the opening being positioned on a same one of the plurality of side walls and the first light and the second light being oriented such that the first light and the second light are visible to the user while the user inhales through the mouthpiece; and a common plane that is generally parallel to the two lateral faces passes through each of the inlet end of the opening, an opening of the mouthpiece, and the first and second lights; and a controller coupled to the first light and the second light, wherein during use the controller activates the first light once the dosage of liquid is within the receiving chamber and the second light after the vibratable element has aerosolized the dosage of liquid and the entire dosage of liquid has been delivered to the user.
 15. The aerosolization system of claim 14, comprising a flow sensor coupled to the controller and configured to detect fluid flow through the mouthpiece as a user inhales, wherein the controller activates the aerosol generator in response to a signal from the flow sensor indicating fluid flow through the mouthpiece, wherein during use the vibratable element aerosolizes the dosage of liquid as the user inhales.
 16. The aerosolization system of claim 14, wherein the liquid receptacle comprises a tapered wall that guides the dosage of liquid to the opening.
 17. The aerosolization system of claim 14, comprises a bottle containing one or more dosages of liquid, and wherein the bottle is configured to dispense the dosage of liquid when the bottle is actuated. 